Aminoglycosides

Amlan Ganguly
Aminoglycoside antibiotics had been the
mainstays for treatment of serious infections due
to aerobic gram-negative bacilli. In contrast to
most inhibitors of microbial protein synthesis,
which are bacteriostatic, the aminoglycosides are
bactericidal inhibitors of protein synthesis.
These agents contain amino sugars linked to an
aminocyclitol ring by glycosidic bonds. They are
polycations, and their polarity is responsible in
part for pharmacokinetic properties shared by all
members of the group.
 Kanamycin

Streptomycin
• Aminoglycosides are natural products or
semisynthetic derivatives of compounds
produced by a variety of soil actinomycetes.
Streptomycin was first isolated from a strain of
Streptomyces griseus. Gentamicin and
netilmicin are broad-spectrum antibiotics
derived from species of the actinomycete
Micromonospora. Tobramycin is produced by S.
tenebrarius.
Mechanism of action:
• Aminoglycosides are irreversible inhibitors of
protein synthesis. The initial event is passive
diffusion via porin channels across the outer
membrane. Drug is then actively transported across
the cell membrane into the cytoplasm by an oxygen-
dependent process. The transmembrane
electrochemical gradient supplies the energy for this
process, and transport is coupled to a proton pump.
Transport may be enhanced by cell wall-active drugs
such as penicillin or vancomycin; this enhancement
may be the basis of the synergism of these
antibiotics with aminoglycosides.
• Inside the cell, aminoglycosides bind to specific
30S-subunit ribosomal proteins. Protein synthesis is
inhibited by aminoglycosides in at least three ways:
• (1) interference with the initiation complex of
peptide formation;
• (2) misreading of mRNA, which causes
incorporation of incorrect amino acids into the
peptide, resulting in a nonfunctional or toxic
protein; and
• (3) breakup of polysomes into nonfunctional
monosomes.
• These activities occur more or less simultaneously,
and the overall effect is irreversible and lethal for
the cell.
Resistance:
• Three principal mechanisms have been established:
• (1) production of a transferase enzyme or enzymes
inactivates the aminoglycoside by adenylylation,
acetylation, or phosphorylation. This is the principal type
of resistance encountered clinically.
• (2) There is impaired entry of aminoglycoside into the
cell. This may be genotypic, i.e., resulting from mutation
or deletion of a porin protein or proteins involved in
transport and maintenance of the electrochemical
gradient; or phenotypic, eg, resulting from growth
conditions under which the oxygen-dependent transport
process described above is not functional.
• (3) The receptor protein on the 30S ribosomal subunit
may be deleted or altered as a result of a mutation.
Therapeutic use:
• Aminoglycosides are mostly used against gram-negative
enteric bacteria, especially when the isolate may be drug-
resistant and when there is suspicion of sepsis. They are
almost always used in combination with a β-lactam
antibiotic to extend coverage to take advantage of the
synergism between these two classes of drugs.
• Bacterial Endocarditis: A combination of penicillin G
and streptomycin may be indicated for treatment of
streptococcal endocarditis.
• Tularemia: Streptomycin (or gentamicin) is the drug of
choice for the treatment of tularemia.
• Plague: Streptomycin is effective agent for the
treatment of all forms of plague.
• Tuberculosis: In the treatment of tuberculosis,
streptomycin always should be used in combination with
at least one or two other drugs to which the causative
strain is susceptible.
 Plague
Endocarditis

Tuberculosis
Adverse effects:
• Ototoxicity: Ototoxicity (vestibular and cochlear) is
directly related to high peak plasma levels and the
duration of treatment. The antibiotic accumulates in the
endolymph and perilymph of the inner ear, and toxicity
correlates with the number of destroyed hair cells in the
organ of Corti. Deafness may be irreversible and has
been known to affect fetuses in utero.
• Nephrotoxicity: Retention of the aminoglycosides by
the proximal tubular cells disrupts calcium-mediated
transport processes, and this result in kidney damage.
• Neuromuscular paralysis: This side effect most often
occurs after direct intraperitoneal or intrapleural
application of large doses of aminoglycosides.
• Allergic reactions: Contact dermatitis is a common
reaction to topically applied neomycin.
Contact dermatitis

Organ of corti
Any question?
Thank you